PROJECT ABSTRACT The goal of this Phase I STTR proposal is to develop and establish preclinical proof-of-concept for the first double chimeric peptide vaccine feasible for human use that protects against disseminated candidiasis. Disseminated candidiasis is the third leading cause of nosocomial bloodstream infections in the US, with 60,000?70,000 cases per year and associated healthcare costs of $2?4 billion; and, despite the availability of antifungal therapy, at least 40% of affected individuals die of the disease. The infection is caused by multiple species of fungal genus Candida with Candida albicans being the most common. In addition, immunocompromising conditions increase susceptibility to the disease. Neutropenia is one of the most common risk factors for the development of disseminated candidiasis in humans, in which the mortality is greater than 50% despite antifungal therapy. Since there is no approved antifungal vaccine for use in humans and current treatments have limited efficacy, the development of novel methods of disease prevention and treatment such as active and passive immunization strategies are critically important. Vaccination of high-risk groups is a particularly promising strategy to prevent invasive Candida infection. An ideal vaccine candidate would 1) target multiple antigenic epitopes to achieve the greatest efficacy and 2) be composed of epitopes that are homologous among medically relevant species of Candida such that universal protection against Candida infection could be achieved rather than against a single species such as C. albicans. Under development currently, there is only one vaccine formulation against Candida albicans (NDV-3; NovaDigm Therapeutics), which has completed Phase I clinical trials. The single-antigen vaccine may prove to provide protection in some cases of disseminated candidiasis; however, it may have limited efficacy in protecting against C. albicans and other medically relevant non-albicans Candida species, including the emerging multi-drug resistant C. auris. This proposal seeks to further the development of a novel double chimeric peptide vaccine that has shown promising results in animal models of disseminated candidiasis. The vaccine is composed of two antigens present in C. albicans as well as other medically relevant species of Candida. The existing vaccine will be ?humanized? by conjugating it to a human approved carrier such as tetanus toxoid and tested in animal models of disseminated candidiasis caused by multiple species of Candida. In addition, since neutropenia is a significant risk factor for development of disseminated candidiasis, the ?humanized? vaccine will be tested for its ability to protect hosts against the disease if an immunocompromising event occurs post-vaccination. The results of the proposed studies will provide non-clinical proof-of-concept for our strategy and will support further development of our double chimeric peptide vaccine.